title: SHPRH and HLTF act in a damage-specific manner to coordinate different forms of postreplication repair and prevent mutagenesis.
abstract: Postreplication repair (PRR) pathways play important roles in restarting stalled replication forks and regulating mutagenesis. In yeast, Rad5-mediated damage avoidance and Rad18-mediated translesion synthesis (TLS) are two forms of PRR. Two Rad5-related proteins, SHPRH and HLTF, have been identified in mammalian cells, but their specific roles in PRR are unclear. Here, we show that HLTF and SHPRH suppress mutagenesis in a damage-specific manner, preventing mutations induced by UV and MMS, respectively. Following UV, HLTF enhances PCNA monoubiquitination and recruitment of TLS polymerase η, while also inhibiting SHPRH function. In contrast, MMS promotes the degradation of HLTF and the interactions of SHPRH with Rad18 and polymerase κ. Our data suggest not only that cells differentially utilize HLTF and SHPRH for different forms of DNA damage, but also, surprisingly, that HLTF and SHPRH may coordinate the two main branches of PRR to choose the proper bypass mechanism for minimizing mutagenesis.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Jia-Ren
authors.initials: JR
authors.lastname: Lin
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Zeman
authors.forename: Jia-Yun
authors.initials: JY
authors.lastname: Chen
authors.forename: Muh-Ching
authors.initials: MC
authors.lastname: Yee
authors.forename: Karlene A
authors.initials: KA
authors.lastname: Cimprich
mesh_terms: D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D057809:HEK293 Cells; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D016296:Mutagenesis; D009153:Mutagens / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
chemical_list: D004265:DNA Helicases; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D008741:Methyl Methanesulfonate; D009153:Mutagens; D018809:Proliferating Cell Nuclear Antigen; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C100023:HLTF protein, human; C485954:RAD18 protein, human; C516226:SHPRH protein, human; C404302:POLK protein, human; D000099270:Y-Family DNA Polymerases